Synthesis of Iron Oxide Nanoclusters by Thermal Decomposition

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Synthesis of iron oxide nanoclusters by thermal decomposition Aleksey A. Nikitin, Igor V. Shchetinin, Natalya Yu. Tabachkova, Mikhail A. Soldatov, Alexander V. Soldatov, Natalya V. Sviridenkova, Elena K. Beloglazkina, Alexander G. Savchenko, Maxim A. Abakumov, and Alexander G. Majouga Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b00753 • Publication Date (Web): 22 Mar 2018 Downloaded from http://pubs.acs.org on March 22, 2018

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Synthesis of iron oxide nanoclusters by thermal decomposition Aleksey A. Nikitin,§,† Igor V. Shchetinin,§ Natalya Yu. Tabachkova,§ Mikhail A. Soldatov,* Alexander V. Soldatov, * Natalya V. Sviridenkova, § Elena K. Beloglazkina,† Alexander G. Savchenko,§ Maxim A. Abakumov,†,‡ Alexander G. Majouga §,†,⁂

§ National University of Science and Technology “MISIS”, Leninskiy prospect 4, 119991 Moscow, Russian Federation † Department of Chemistry, Lomonosov Moscow State University, Leninskiye gory 1-3, GSP-1, 119991 Moscow, Russian Federation *Southern Federal University, Bolshaya Sadovaya st., 105, 344006 Rostov-on-Don, Russian Federation ‡ The Russian National Research Medical University, Ostrovityanova 1, 117997 Moscow, Russian Federation ⁂Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya 9, 125047, Moscow, Russian Federation

ABSTRACT. Herein, we report a novel one-step solvothermal synthesis of magnetite nanoclusters (MNCs). In this report we discuss synthesis, structure and properties of MNCs and contrast enhancement in T2-weighted MR images using magnetite nanoclusters. Effect of different organic acids, used as surfactants, on size and shape of MNC was investigated. Structure and properties of samples were determined by magnetic measurements, TGA, TEM, HRTEM, XRD, FTIR, MRI. Magnetic measurements show that obtained MNCs have relatively high saturation magnetization values (65.1 – 81.5 emu/g) and dependence of the coercive force on the average size of MNCs was established. MNCs were transferred into aqueous medium by Pluronic F-127 and T2-relaxivity values were determined. T2-weighted MR phantom images clearly demonstrated that such magnetite nanoclusters can be used as contrast agents for MRI.

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1. INRODUCTION The development of nanoparticle-based systems for diagnostic and therapeutic purposes is one of emerged areas in modern biomedicine. From a number of different nanomaterials magnetic iron oxide nanoparticles are certainly the most promising material for biomedical applications, including high frequency magnetic field hyperthermia, application as T2-contrast agents in MRI, as drug carriers for targeted delivery, cell-labeling and others

1,2

. The shape is one of the most

important factors in determining the biological properties of nanoparticles

3–5

. Shape-controlled

synthesis of nanoparticles has become a recent focus, because different shapes of particles can introduce novel magnetic and electric properties, which affect the parameters required for biomedical application, such as MRI and hyperthermia. Much effort has been focused recently on the synthesis of uniform nanoparticles with various shapes, such as spheres and cubes 6–11. The first mention about synthesis of iron-oxides colloidal nanocrystal clusters was made by the group of S.A. Asher 12. In this work polymerization of pre-synthesized iron oxide nanoparticles in the presence of polystyrene was used to produce iron oxide nanoclusters. A lot of research groups focused their attention on colloidal nanocrystal clusters because the controlled assembly of initial small magnetic nanoparticles into cluster structures with defined shape and size opens horizons for materials which combine properties of individual nanocrystals as well as collective properties due to interactions between the single units. Such iron oxide cluster structures are a very perspective material for various technological and biomedical applications such as separation, catalysis, diagnostics and treatment of cancer and many others 13,14. Many research groups synthesized magnetite nanocrystal clusters with various sizes through thermal decomposition of iron (III) chloride in ethylene glycol with addition of different substances such as sodium and ammonium acetate, polyethylene glycol, ethylenediamine, sodium citrate, polyacrylic acid, urea 15–17 and microclusters 18–20. Furthermore such nanocrystal clusters can be used for MRI application 21–24. Moreover in vitro testing and drug delivery with such nanoclusters were performed 17,24,25. Cho et. al. demonstrated 2 ACS Paragon Plus Environment

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that assemblies of iron oxide nanocubes (with average diameter of 100 nm) exhibited high T2relaxivity and heating efficiency 26. This paper presents, for the first time, a modified thermal decomposition method that involves self-assembly of magnetite nanoparticles and results in highly ordered cubic or flowerlike magnetite nanoclusters with a controlled size in a suitable for biomedical application size ranges. Influence of the different organic acids as surfactants on a shape and size of nanoclusters was investigated. In addition, T2-weighted MR phantom images clearly demonstrated that such nanoclusters can be used as contrast agents for MRI. 2. EXPERIMENTAL SECTION 2.1. Materials. Iron (III) acetylacetonate (Fe(acac)3; ≥99.9%), benzyl ether (98%), oleic acid (OA; tested according to Ph. Eur.), 1,2-hexadecanediol (1,2-HDIOL; technical grade, 90%), cyclopropanecarboxylic acid (95%), cyclobutanecarboxylic acid (98%), cyclopentanecarboxylic acid (99%), cyclohexanecarboxylic acid (98%), benzoic acid (≥99.5%), biphenyl-4-carboxylic acid (95%), ammonium acetate (99.99%), 3-(2-Pyridyl)-5,6-diphenyl-1,2,4-triazine-p,p′disulfonic acid monosodium salt hydrate (Ferrozine; 97%), L-ascorbic acid (≥99.0%), Pluronic F127 and dichloromethane (≥99.8%) were purchased from Sigma-Aldrich. 1-Indanecarboxylic acid (95%) was purchased from ABCR GmbH & Co. KG. Hexane (≥98.0%), 2-propanol (≥99.8%) and nitric acid (HNO3; ≥65.0%) were purchased from Component-Reaktiv (Moscow, Russia). Hydrochloric acid (HCl; 36%) was purchased from Sigma Tek (Moscow, Russia). All reagents were used without any further purification. Ultra-pure Milli-Q water was obtained by means of Millipore Milli-Q Academic System. All glassware used for synthesis of all samples were cleaned with hot aqua regia (v(HCl)/v(HNO3) = 3/1) and then washed with Milli-Q water. 2.2. General approach to the synthesis of MNCs. The mixture of Fe(acac)3 (2 mmol), 1,2HDIOL (8 mmol) and different organic acids (see Table 1) in benzyl ether (20 ml) were placed in a round bottom flask (50 ml) equipped with thermometer and reflux condenser. For removing of oxygen and trace amounts of water from reaction medium, the solution was warmed up to 130°C 3 ACS Paragon Plus Environment

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under argon flow and magnetic stirring and maintained for 1 h. Then the mixture was heated to 210°C with a rate about 5°C/min and kept at this temperature for 1 h. After that, the temperature was raised to 260°C with a rate of 5°C/min and kept at this temperature for 30 min. Then the source of heat was removed and solution was cooled down to the room temperature. MNCs were collected by centrifugation (6000 rpm, 30 min) after adding 10 ml of mixture 2-propanol – hexane (v/v = 1/1). Finally, MNCs were redispersed in dichloromethane (20 ml) and stored at 4°C. 2.3. Synthesis of water soluble MNCs (MNCs@Pluronic F-127). For transfer of MNCs from organic to aqueous medium they were conjugated with Pluronic F-127. For this purpose Pluronic F-127 (1.6 µmol) was dissolved in Milli-Q water (4 ml) and 2 ml of MNCs in dichloromethane ([Fe] = 2.5 mg/ml) was added to this solution. Resulting mixture was heated to 40°C under argon flow to evaporate the dichloromethane. After that MNCs@Pluronic F-127 were collected by ultracentrifugation (14000 rpm) and redispersed in Milli-Q water. This procedure was repeated several times to purify MNCs@Pluronic F-127 from unreacted Pluronic F-127. 2.4. Characterization of MNCs by TEM and HRTEM. Transmission electron microscopy (TEM) images of synthesized MNCs and high-resolution transmission electron microscopy (HRTEM) images were taken on JEOL JEM-1400 (120 kV) and JEM-2100 (200 kV) microscopes respectively. All samples were prepared by dropping dichloromethane dispersion of synthesized samples onto a carbon-coated copper grid (300 mesh) and subsequently evaporating of the solvent. The average diameter of the samples and size distribution were evaluated by using ImageJ software. At least 1000 NPs were analyzed for each sample. 2.5. Characterization of MNCs by XRD spectroscopy. XRD patterns at room temperature were obtained using an X-ray power diffractometer DRON-4 with Co Kα radiation. The data were collected from 2θ = 20 to 140° at a scan rate 0,1° per step and 3 s per point. Qualitative phase analysis was performed by comparison of obtained spectra with PHAN database. Quantitative analysis (including crystal size evaluation by determination of coherent-scattering region) was


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performed using PHAN% and SPECTRUM programs developed by Physical Materials Science Department of NUST «MISiS» (modification of Rietveld method). 2.6. Characterization of MNCs by magnetic measurements. M-H hysteresis loops (from -30 to 30 kOe, 300 K) were obtained on «Quantum Design» Physical Property Measurement System (PPMS) equipped with vibration magnetometric device (VSM) with 2 mm amplitude of oscillations, 40 Hz frequency. 2.7. Characterization of MNCs by Mössbauer spectroscopy. Mössbauer spectra of

57

Fe

nuclei at room temperature were recorded with MS-1104Em spectrometer in transmission geometry with

57

Co(Rh) source of radiation. Spectra analysis was performed by Univem MS

program and values of effective magnetic fields Heff, isomer shifts δs, quadrupole splitting Δ of elementary spectra and their relative intensity (area) were determined. 2.8. Characterization of MNCs by TGA. Thermogravimetric curves were recorded on synchronous thermogravimetric analyzer Netzsch STA 449 F3. In a typical procedure 5 mg of samples were heated in corundum crucibles under argon flow in temperature range 50 – 800°С with a heating rate of 10 °С/min. 2.9. Characterization of MNCs by MRI. T2-relaxation rate of water protons in the presence of MNCs covered with Pluronic F-127 was measured in 500 μl test tubes at 18°С on a ClinScan 7T MRI system. Image acquisition was performed in Spin Echo mode with following parameters: MRI system TR = 10000 ms, TE = 8, 16, 24, 240 ms, flip angle = 180 deg, resolution 640x448 pixels, field of view FOV = 120x82.5 mm2. Signal intensities from regions of interest were manually measured by Image J software and T2-relaxation time was calculated by fitting signal from images with different TE. T2-relaxivity values were calculated using a linear fitting of 1/T2 relaxation times to iron concentration. The slope of fitting curve represents the R2-value for MNCs covered with Pluronic F-127 used for MR imaging. The concentration of iron ions in each sample was determined using a standard ferrozine-based assay protocol 27.


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2.10. Characterization of MNCs by HERFD XANES. High Energy Resolution Fluorescence Detected X-ray Absorption Spectra (HERFD XANES) of Fe K-edge of MNCs were measured at ID26 undulator beamline of European Synchrotron Radiation Facility (ESRF). The incident energy was monochromized by Si(311) crystals. In order to measure HERFD-XANES spectra at the Fe K edge a set of four spherically bent Ge(440) crystals were used to deliver a Fe Kα1 emission line maximum photons to the avalanche photodiode. The spectra were area normalized prior to analysis. 2.11. Characterization of samples by FTIR spectroscopy. FTIR spectra of samples were registered by means of Nicolet 380 (Thermo Scientific, USA), in KBr, in the range 400 – 4000cm-1. Infrared spectra were obtained by the KBr pellet method. In this method, the solid sample is finely pulverized with pure, dry KBr, the mixture is pressed in a hydraulic press to form a transparent pellet, and the spectrum of the pellet is measured. 3. RESULTS AND DISCUSSION 3.1. Synthesis of magnetite nanoclusters MNCs. Previously two possible ways to prepare colloidal nanocrystal clusters were described: the two-step procedure that includes synthesis of individual nanoparticles (nanocrystals) and their further aggregation in a controllable way 28,29 and the one-step protocol that combines the synthesis of nanoparticles and their aggregation into clusters

30,31

. In the present work, for the synthesis of colloidal nanocrystal clusters based on

magnetic nanoparticles we used decomposition process of iron-containing precursor such as iron (III) acetylacetonate in organic medium (Scheme 1). In all cases reaction parameters such as amount of iron precursor and 1,2-HDIOL, temperature, heating and stirring rate were identical, whereas the nature of surfactants (organic acids) using for stabilization and shape control of MNCs during synthesis process was different.


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Scheme 1. Schematic presentation of synthesis of colloidal clusters.

Previously the effect of bulky adamantane group on the formation of colloidal magnetite nanoclusters in the presence of 1-adamantanecarboxylic acid was described

30

. The effect of

structure and nature of carboxylic acid substituent on the formation of MNCs was not clear until the end, as well as mechanism of the MNCs formation. Herein, for the first time, we used less hindered

acids

(cyclopropanecarboxylic,

cyclobutanecarboxylic,

cyclopentanecarboxylic,

cyclohexanecarboxylic, benzoic, biphenyl-4-carboxylic and 1-indanecarboxylic) with pure alicyclic and aromatic fragments, as well as mixed one (Table 1). Samples A, C, E, G, I, K, M were prepared using mixture of oleic acid (6 mmol) and other organic acid (6 mmol) (molar ratio = 1:1).


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Table 1. Organic acids used for synthesis of MNCs

Samples

A

B

C

D

E

F

G

H

I

J

K

L

M

N

Acids Oleic Cyclopropanecarboxylic Cyclobutanecarboxylic Cyclopentanecarboxylic Cyclohexanecarboxylic Benzoic Biphenyl-4-carboxylic 1-Indanecarboxylic

3.2. Characterization of MNCs by TEM and HRTEM. The size and morphology of obtained samples were studied by TEM and HRTEM (Figure 1). From TEM images of synthesized it was found that the samples A, B, D, F, J, K and N represent cluster-like nanostructures with various shape and structure of individual nanoparticles (Figure 1). Samples C, E, G, H, I, M are faceted spheres with different size. The sample L is truncated cubes. Histograms of size distribution of obtained MNCs are presented in Figure S1.


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Figure 1. TEM images of synthesized samples.

It was discovered that, the nature of organic acid affects the morphology of individual magnetic nanoparticles as well as on the structure of MNCs. Thereby, depending on the nature of the organic acid we obtained nanomaterials with different structure. The formation mechanism of nanoclusters is not completely clear. As discussed in the literature if the fusion of nanoparticles is prevented by separation with capping molecules or other reasons, then mesocrystals are formed 32. For example, Hugounenq et al. 33 synthesized iron oxide nanoflowers in the presence of DEG and NMDEA. The structure of obtained nanoflowers contains defect holes. The authors suggest that 10 ACS Paragon Plus Environment

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such defect holes contain traces of solvents used for the synthesis (DEG and NMDEA) which are responsible for MNCs formation. We believe that in the case of MNCs A, B, D, F, J, K and N nanocluster formation occurs from pre-obtained individual magnetic nanoparticles during the synthesis. The proof of formation is the presence of individual nanoparticles in TEM images as well as the clear distance between nanoparticles in the nanocluster. According to the Fu’s concept

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the key step of nanocluster

formation is adsorption-desorption process of organic ligands on the surface of initial nanoparticles. In Table 2 the basic characteristics of cyclocarboxylic acids used in the synthesis are presented.

Table 2. The basic characteristics of cyclocarboxylic acids Acid

logP

Boiling point,°C

Cyclopropanecarboxylic

0.48

182-184

Cyclobutanecarboxylic

0.87

195

Cyclopentanecarboxylic

1.26

216

Cyclohexanecarboxylic

1.89

231-233

Benzoic

1.87

249

1-Indanecarboxylic

1.79

325

Biphenyl-4-carboxylic

3.75

373

Oleic

6.78

360

In the step of nucleation and growth of nanoparticles the organic acid participates in multiple adsorption-desorption process. Moreover, the amount of desorbed acid will be higher in the case of an organic acid having a greater affinity for the solvent - benzyl ether (logP 3.95). Among all used cyclocarboxylic acids cyclopropanecarboxylic acid has the lowest affinity to benzyl ether (Table 2). To investigate effects of acid adsorption on growing seeds we have additionally made synthesis in mixture of organic acid and oleic acid in order to check if partial substitution by oleic acid will result in identical nanostructures. It is interesting that in the case of 11 ACS Paragon Plus Environment

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pure cyclopropanecarboxylic acid and mixture of cyclopropanecarboxylic and oleic acid spherical clusters with identical structure and average size were obtained. Most probably initially nucleating seeds of iron oxide were stabilized by oleic and cyclocarboxylic acids. Then cyclocarboxylic acid may be desorbed on free areas of nanoparticles or it can diffuse to the surface, displacing oleic acid. However, cyclopropanecarboxylic acid has the lowest value of logP = 0.48 among all aliphatic cyclocarboxylic acids and therefore it is firmly fixed to the surface of nanoclusters, whereas oleic acid is presented in solution. The nature of cyclocarboxylic acids and values of logP affect the size and morphology of obtained nanoparticles.

With increasing

logP

from

cyclopropanecarboxylic

acid

to

cyclohexanecarboxylic acid in the presence of oleic acid we have not detected formation of nanoclusterss.

Cyclobutanecarboxylic

acid

molecules

have

the

bigger

size

than

cyclopropanecarboxylic acid molecules. Moreover the value of logP for cyclobutanecarboxylic acid is 0.87, which approximately two times larger than for cyclopropanecarboxylic acid. Thus cyclobutanecarboxylic acid molecules have more affinity to the solvent. In can be seen from Figure 1 there are a lot of free nanoparticles with non-cluster nature in the Sample C. Moreover the crystallites size of Sample C is less in comparison with Sample A which can be explained by the fact that on the surface of particles more and more molecules of oleic acid are located, which prevent their subsequent adhesion with the formation of nanoclusters. Cyclopentanecarboxylic and cyclohexanecarboxylic acids have even higher values of logP in comparison with cyclopropanecarboxylic acid (approximately 2 and 3 times, respectively). Thus, these acids are even less fixed on the surface of the particles and are easily replaced by oleic acid. Thereby, the diffusion of iron ions to the surface of growing crystals is complicated, which results in the formation of small non-clustered nanoparticles (samples E and G). When pure cyclopropanecarboxylic acid (Sample A) is used, cluster nanoparticles are formed from large crystallites due to the fact that this acid has a small molecule size and does not prevent diffusion of iron ions to the surface of growing nanoparticles. The same observation can 12 ACS Paragon Plus Environment

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be made in the case of cyclobutanecarboxylic acid (Sample D). Cyclopentanecarboxylic acid (sample F) has larger aliphatic tail that complicates the diffusion of Fe3+ ions, resulting in clusters having a smaller crystallite size. Cyclohexanecarboxylic acid having a higher value of logP = 1.89 is readily desorbed into the solution, and therefore the surface of the nanoparticles becomes more available for Fe3+ ions. Thus, the diffusion of Fe3+ ions proceeds easily, which leads to the formation of large nanoparticles. Mixture of benzoic and 1-indacarboxylic acid with oleic acid results in the situation similar to the examples discussed above. Biphenyl-4-carboxylic acid has the highest value of logP = 3.75 among all cyclocarboxylic acids. In the case of pure biphenyl-4carboxylic (Sample L) cluster morphology is not observed due to the easy desorption of the acid to the solution. To confirm that 1,2-HDIOL doesn’t effect on the formation of nanoclusters, synthesis of MNCs only in the presence of 1,2-HDIOL and oleic acid was performed. As a result, only nanoparticles with truncated sphere morphology were obtained (SI, Figure S2). All samples were synthesized under other heating rate conditions. As seen from TEM (SI, Figure S3) fast heating of the reaction mixture results in formation of smaller MNCs. Previously such effect was observed during synthesis of magnetite nanoparticles and explained by formation of a great number of magnetite seeds 35. In contrast to most published MNCs examples all synthesized samples lie in nanosized region. MNCs A and B have the similar structure and the same average size of nanoclusters. Among all synthesized MNCs A, B and N represent the most interest due to their clear cluster morphology. Thus, the most complete physicochemical studies were carried out for these MNCs. More details about the structure of MNCs with unusual morphology were obtained from HRTEM (Figure 2). As we can see from HRTEM images of MNCs A and MNCs N individual clusters randomly disoriented relatively to the direction of the primary beam, but inside they are composed of sufficiently perfect single-crystal particles with similar orientation (Figure 2(1),(2)).


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Also, from FFT images it is clearly seen that the orientation of the particles in each cluster is very close (Figure 2(4),(5)).

Figure 2. HRTEM images of: (1) MNCs A, (2) MNCs N; cluster formation process for Sample N (3); Fourier transform (FFT) images of: (4) MNCs A and (5) MNCs N; (6) individual cubic particle of MNCs N. The distance between two planes in individual particles in a specific direction is 0.297 nm, which is most likely the lattice spacing of (220) planes of Fe3O4 phase (Figure 2(6)). MNCs A and N differ in shape and density. MNCs N are more friable, the particles are joined together to form voids. The shape of MNCs A is close to spherical and MNC Ns is close to cubic. Moreover in case of MNCs N in Figure 2(3) it can be seen that the cluster growth process begins with aggregation 14 ACS Paragon Plus Environment

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of a small number of nanoparticles, which proves that the mechanism of MNCs N formation is related to self-assembling process. By the way, some free nanoparticles were found in the final products which argue that the MNCs were formed by oriented aggregation but not by splicing the individual particles with each other.

Figure 3. TEM images of individual magnetite nanoparticles (marked out area) in as-synthesized MNCs A and N.

Thus we suggest that utilized acids are located in nanocluster defect holes as well as are attached to the surface of individual nanoparticles in nanocluster. To confirm this suggestion the Fourier transform infrared (FTIR) spectroscopy for all obtained samples were performed (Figures 4-7). Figures 4 and 5 show the FTIR spectra of samples synthesized in the presence of pure aliphatic

cyclocarboxylic

acids

(cyclopropane,

cyclobutane,

cyclopentane

and

cyclohexanecaboxylic acids) and their mixture with oleic acid respectively. The main bands at 585, 1420, 1637, 2852, 2923 and 3432 cm-1 have appeared in FTIR spectrum of samples. In Figure 4 the band at 585 cm-1 corresponds to the vibration of the Fe–O bonds in all samples 36. This band also occurs in all recorded spectra (Figure 4-7). The peaks of 1420 cm-1 are consistent with the stretching vibration of the carboxyl groups and occurs in every cyclocarboxylic FTIR spectra 37,38. In oleic acid this band is present in the form of a doublet with similar intensities of each peak (1413 cm-1 and 1458 cm-1) (SI, Figure S4). The band at around 3432 cm−1 is attributed to the stretching 15 ACS Paragon Plus Environment

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modes of H2O molecules which are most likely present in KBr. Also the band at around 1635 cm−1 can be assigned to the bending vibrations of H2O 39. Furthermore different peaks in the range of 1026 cm-1 – 1420 cm-1 confirm presence of utilized cyclocarboxylic acids in MNCs (SI, Figure S5 – S11). Peak at 1735 cm-1 corresponds to vibration of C=O stretching.

Figure 4. FTIR spectra of samples B, D, F and H.

Comparing FTIR spectra of nanoparticles synthesized using pure aliphatic cyclocarboxylic acids with FTIR spectra of nanoparticles synthesized in the presence of a mixture of such acids with oleic acid we can see an increase in the band intensity at 1097 cm-1 in the homologous series of aliphatic acids, starting with cyclopropanecarboxylic acid (Figure 5). This band is present in FTIR spectrum of nanoparticles obtained in pure oleic acid (SI, Figure S12). As discussed above with increasing size of aliphatic cyclocarboxylic acid the cluster nature of the obtained samples disappears (Samples A, C, E, G).


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Figure 5. FTIR spectrum of magnetic nanoclusters.

In the case of pure benzoic, biphenyl-4-carboxylic and 1-indanecarboxylic acids it is also possible to observe characteristic bands of each acid. For example, in the case of biphenyl-4carboxylic acid (Sample L) we can observe characteristic bands from 1000 cm-1 to 1200 cm-1 (two doublets and singlet) which is in good agreement with data obtained from biphenyl-4-carboxylic FTIR spectrum. It should be noted that, because of the large number of peaks in the spectra of cyclic aromatic acids, it is difficult to establish any obvious changes in the spectra of samples synthesized with and without oleic acid addition (Figures 6 and 7).


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3.3. XRD, Mössbauer spectroscopy and HERFD XANES of samples. The X-ray diffraction pattern of MNCs A is shown in Figure 8. All synthesized MNCs have identical XRD patterns (Figure S13). The peaks can be indexed at 35.10°, 41.41°, 43.35°, 50.48°, 62.97°, 67.28°


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and 74.18° corresponding to the crystal planes of {220}, {311}, {222}, {400}, {422}, {511} and {440} respectively.

Figure 8. XRD pattern of MNCs A with the indexation of the Bragg peaks to an inverse spinel structure.

The position and relative intensity of all diffraction peaks can be indexed to a Fe3O4 (a = 8,396 Å, JCPDS no.19-0629) or γ-Fe2O3 (a = 8,346 Å, JCPDS 39-1346) phases. XRD characteristics of obtained MNCs are presented in Table 3.

Table 3. XRD characteristics of MNCs.

X-ray diffraction analysis Sample

Volume fraction, %

Crystallite size, nm

Lattice constants, nm

A B D F J K N

Fe3O4 100 100 100 100 100 100 100

Fe3O4 18.4(3) 16.4(3) 13.3(4) 10.1(5) 15.9(3) 12.7(2) 10.8(5)

Fe3O4 0.8392(6) 0.8396(3) 0.8387(3) 0.8384(12) 0.8407(18) 0.8390(9) 0.8399(10)


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It’s well known that according to the XRD data it’s difficult to distinguish Fe3O4 and γFe2O3 phases. In order to prove the formation of magnetite phase, the Mössbauer spectra for MNCs A and N are registered at the room temperature. The recorded spectra have the form of asymmetric sextets (Figure 9).

.

Figure 9. Room temperature Mössbauer spectra of MNCs A and MNCs N.


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Parameters of the hyperfine structure components of Mössbauer spectra are shown in the Table S1. In order to describe the structure of MNCs more accurately the calculation of obtained spectra was carried out (Table 4). As shown, the Mössbauer spectra of the resulting materials confirms that the two sextuplets are due to the small difference between the hyperfine fields of the Fe3+ and Fe2+ ions in the sublattices for octahedral and tetrahedral sites. No signals due to the existence of other phases such as maghemite are observed.

Table 4. Mössbauer parameters obtained from experimental spectra

A

Mössbauer spectrum area of Fe3+ ions in tetrahedral site (Sa) 35.78

Mössbauer spectrum area of Fe2+ ions in octahedral site (Sb) 64.22

N

40.82

59.18

MNCs

Sb/Sa (σ)

Vacancy parameter (k)

Fe2+/Fe, %

1.7948

0.01

33

1.4498

0.04

30

Crystal-chemical formula for Fe3O4 can be written as Fe3+[Fe2+1-3kFe3+1+2k φk]O4 where φ stands for a vacancy and k is a vacancy parameter. A feature of the Mössbauer spectra of nonstoichiometric magnetite is the distribution of the electron exchange between ions Fe3+ and Fe2+ in the octahedral positions in the presence of vacancies. At the same time some of the ions Fe3+, that are not involved in such exchanges because of Fe2+ ions deficit, form a spectrum which is not distinguishable from a Mössbauer spectrum of Fe3+ ions in the tetrahedral positions. As a result, if we consider the probability of resonance effect of iron ions in the tetrahedral and octahedral positions as equal then for the Sa/Sb ratio can be written as 40:

𝜎=

𝑆𝑏 2 − 6𝑘 = 𝑆𝑎 1 + 5𝑘

Sa and Sb – Mössbauer spectra areas of Fe3+ ions in tetrahedral and octahedral sites, respectively. Thereby vacancy parameter k can be calculated as: 21 ACS Paragon Plus Environment

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𝑘=

Page 22 of 34

2−𝜎 6 + 5𝜎

Thus, the vacancy parameter takes values equal to hundredths (Table 4) which means that all synthesized MNCs are pure magnetite. Also for MNCs A and N the high energy resolution fluorescence detected X-ray absorption spectra (HERFD XANES) were registered. Fe K-edge XANES spectra are very sensitive to electronic configuration of iron ions and is a direct probe of the oxidation state Fe2+ and Fe3+ ions. The later could shed light on the iron oxide magnetic nanoparticle phase composition, particularly it is capable of distinguishing between two spinel phases in small nanoparticles: magnetite and maghemite. Figure 10A shows HERFD XANES spectra of samples MNCs N and MNCs A in comparison to reference γ-Fe2O3 and Fe3O4.

Figure 10. (A) HERFD XANES spectra of MNCs A (green line) and MNCs N (blue line) samples compared to reference Fe3O4 (black line) and γ-Fe2O3 (red line). (B) Pre-edge region of HERFD XANES spectra. (C) The first derivative of HERFD XANES spectra. 22 ACS Paragon Plus Environment

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It is clearly visible that MNCs N is almost identical to Fe3O4, however MNCs A spectrum shows blue shift due oxidation state. In order to obtain a quantitative information on the electronic configuration of iron a linear combination fit of reference sample spectra were performed. MNCs A seems to be a mixture of Fe3O4 (91.8%) and γ-Fe2O3 (8.2%), while MNCs N is almost totally Fe3O4 (99.6%). The remaining 0.4% refer to the phase γ-Fe2O3. 3.4. Magnetic properties of MNCs. The main magnetic parameters of synthesized MNCs are reported in Table 5. Magnetic hysteresis measurements are carried out at 300 K and normalized to Fe3O4 content determined using TGA (Figure S14). The degradation of organic acids occurs in the range from 150°C to 500°C. Furthermore, degradation of all organic acids used in the synthesis of MNCs also takes place in this range. Weight reduction at the range above 500°C is most likely due to the magnetite phase transformation processes 41. Table 5. Magnetic parameters of synthesized samples MNCs

Size, nm

K F D J N B A

23 25 31 32 38 40 41

Crystallite size, nm 12.7(2) 10.1(5) 13.3(4) 15.9(3) 10.8(5) 16.4(3) 18.4(3)

Hc, Oe 0.2 9.0 15.3 17.5 34.5 49.0 55.0

Magnetic properties Mr, emu/g 2.1 0.9 1.4 1.6 4.5 4.3 4.2

Ms, emu/g 65.1 78.1 77.2 77.8 77.4 80.5 81.5

The hysteresis curves (M–H responses) for MNCs are shown in Figure 11.


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Figure 11. (A) Room temperature magnetization curves of MNCs obtained using a magnetic field from -30 to 30 kOe and (B) low-field portion showing HC values.

The Figure 11A indicates that all synthesized MNCs have relatively high saturation magnetization Ms values from 65.1 to 81.5 emu/g (for bulk magnetite this value is 91 emu/g). These samples consist of magnetite nanoparticles with average size from 10.1 to 18.4 nm (XRD analysis). High saturation magnetization of these samples can be explained by magnetostatic 24 ACS Paragon Plus Environment

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interactions between individual magnetite nanoparticles which lead to increase of magnetic anisotropy of nanoparticles complex

42

. Consequently nanoparticles in superparamagnetic state

turn into magnetically ordered state which increases saturation magnetization. Recently Lee et al.43 synthesized spherical MNCs with different size (from 16 to 512 nm) via a hydrolysis condensation and reductive polyol process and studied their magnetic properties. For example, for MNCs with size 32 nm the values of coercivity and magnetization were 0.57 Oe and 60.4 emu/g respectively. In our case MNCs J with average size 32 nm has coercivity 17.5 Oe while magnetization is 77.8 emu/g. Moreover the highest value of Ms (80.4 emu/g) in Lee’s work were obtained for MNCs with diameter 422 nm. In our work we obtained such magnetization for MNCs B with size 40 nm. The maximum coercivity value was obtained for MNCs A with size 41 nm (55 Oe) whereas the maximum coercivity in Lee’s work was demonstrated for 123 nm MNCs. Figure 11B shows that MNCs are ferromagnetic at room temperature except for MNCs K which are ferrimagnetic. The magnetic coercivity does not exceed 55.0 Oe for MNCs A with average size 41 nm. Figure 12 displays the HC variation of MNCs as a function of their average size. The values of coercivity HC increase with increasing size of MNCs as well as the values of saturation magnetization MS, which is in agreement with previously published data for magnetic nanoclusters 43

.


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Figure 12. Curves of saturation magnetization (Ms) and coercive force (Hc) from average size of samples obtained by TEM analysis.

3.5. MRI with water soluble MNCs. MNCs A and N were transferred into aqueous medium by copolymer Pluronic F-127 and T2 relaxivity was determined. For synthesis of water soluble MNCs they were conjugated with Pluronic F-127. We used Pluronic F-127 to decorate MNCs nanoparticles because it’s a copolymer which

consists

of

poly(ethyleneoxide)-poly(propyleneoxide)-poly(ethyleneoxide)

blocks.

Hydrophilic corona prevents aggregation, protein adsorption and RES recognition. Moreover, micelles based on Pluronic block copolymers can improve the sensitivity of multidrug resistant cancer cells to the anticancer chemotherapy 44. The results of size measurement using DLS show that the hydrodynamic diameter of the MNCs after coating with Pluronic F-127 is about 100 nm (SI Figure S15). This is due to the fact that the MNCs are collected in small micelles. Plots of R2 values and T2 – weighted MR images of MNCs at various concentrations of iron are presented in Figure 13.


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Figure 13. MR contrast effect of MNCs. (A) Plots of R2 values of MNCs and (B) T2 – weighted MR images of MNCs at various concentrations of iron.

The T2-weighted MR images show that MNCs N has the most expressed T2-contrast, compared with MNCs A (Figure 13B). Probably, this fact can be explained by cubic shape of MNPs consisting MNCs. Lee and colleagues demonstrated very high r2 values for cubic magnetite nanoparticles 8. The r2 values of MNCs A and MNCs N were 104 and 168 s-1 mM-1 respectively. Comparing with other MNCs (Table 6) we can conclude that our MNCs are very perspective materials for MRI investigations. Table 6. MNCs as contrast agents in MRI Clusters

Nanocluster size (nm)

Method

Coating agent

r2 (mM-1s-1)

Iron oxide 22

13 36

TEM

Poly(acrylic acid)

240 540

Iron oxide 45

50

TEM

Poly(dopamine)

160.68 27

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Page 28 of 34

Double Hydrophilic Copolymer (PAM-PTEA) Oleic acid (OA) / Oleylamine in Amphiphilic Copolymer

γ–Fe2O3 46

127

DLS

Fe3O4 47

58

DLS

68

TEM

SDS

270

73 41 38

TEM TEM TEM

PLGA-PEG Pluronic F-127 Pluronic F-127

333 104 168

Densely packed SPIONs γ –Fe2O3/Fe3O4 48 Fe3O4 49 MNCs A (Fe3O4) MNCs N (Fe3O4)

91

117

The smaller values of the Т2 relaxivity in comparison with the previously obtained MNCs can be explained by the thickness of the polymer shell. Previously it was shown that increasing the size of the polymer shell leads to a decrease in the T2 relaxivity values 50. Pluronic F-127 has a large molecular weight (12500 Da) and size which is most likely leads to a decrease in Т2 relaxivity values. Nevertheless, the Т2 values of obtained MNCs are comparable with the T2 values of commercial contrast agents based on iron oxide nanoparticles

51

. Thus obtained MNCs are

promising contrast agents for MRI investigations. 4. CONCLUSIONS In this manuscript we report one-step new method for synthesis of MNCs based on thermal decomposition of iron precursor in the presence of different organic acids. The results show that the different organic acids can directly affect the final shape and size of the MNCs through the specific absorption onto surface of magnetite nanocrystals. By this method we obtained magnetite nanoclusters with different shape and size. Using FTIR-spectroscopy, we proved the presence of the organic acids in the structure of MNCs. Magnetic measurements of obtained MNCs showed the high values of saturation magnetizations values (65.1 – 81.5 emu/g). MRI studies have revealed high potential of Pluronic F-127 coated MNCs as T2 contrast agents. ASSOCIATED CONTENT


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Supporting Information. Figure S1: Histograms of size distribution of obtained MNCs. Figure S2: TEM image of MNPs (13±2 nm) synthesized in the presence of 1,2 -HDIOL and oleic acid. Synthesis of spherical MNCs with average size of 21 nm. Synthesis of cubic MNCs with average size of 31 nm. Figure S3: TEM images of synthesized MNCs A with average size 21±3 nm (A) and MNCs N with average size 31±8 nm (B). Figure S4. FTIR spectrum of oleic acid. Figure S5. FTIR

spectrum

of

cyclopropanecarboxylic

acid.

Figure

S6.

FTIR

spectrum

of

cyclobutanecarboxylic acid. Figure S7. FTIR spectrum of cyclopentanecarboxylic acid. Figure S8. FTIR spectrum of cyclohexanecarboxylic acid. Figure S9. FTIR spectrum of benzoic acid. Figure S10. FTIR spectrum of biphenyl-4-carboxylic acid. Figure S11. FTIR spectrum of 1indanecarboxylic acid. Figure S12. Nanoparticles obtained in the presence of pure oleic acid. Figure S13. XRD patterns of samples B, D, F, J, K and N. Table S1. Parameters of the hyperfine structure components obtained from the experimental Mössbauer spectra. Figure S14. TG curves of MNCs. Figure S15. DLS measurements of MNCs A and N after conjugation with Pluronic F127. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mails: [email protected], [email protected] Notes The authors declare no competing financial interest. Author Contributions This manuscript was written through contribution of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT


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Graphical Abstract


Synthesis of Iron Oxide Nanoclusters by Thermal Decomposition

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